Endogenous tetrahydroisoquinolines associated with Parkinson's disease mimic the feedback inhibition of tyrosine hydroxylase by catecholamines.

Abstract

N-methyl-norsalsolinol and related tetrahydroisoquinolines accumulate in the nigrostriatal system of the human brain and are increased in the cerebrospinal fluid of patients with Parkinson's disease. We show here that 6,7-dihydroxylated tetrahydroisoquinolines such as N-methyl-norsalsolinol inhibit tyrosine hydroxylase, the key enzyme in dopamine synthesis, by imitating the mechanisms of catecholamine feedback regulation. Docked into a model of the enzyme's active site, 6,7-dihydroxylated tetrahydroisoquinolines were ligated directly to the iron in the catalytic center, occupying the same position as the catecholamine inhibitor dopamine. In this position, the ligands competed with the essential tetrahydropterin cofactor for access to the active site. Electron paramagnetic resonance spectroscopy revealed that, like dopamine, 6,7-dihydroxylated tetrahydroisoquinolines rapidly convert the catalytic iron to a ferric (inactive) state. Catecholamine binding increases the thermal stability of tyrosine hydroxylase and improves its resistance to proteolysis. We observed a similar effect after incubation with N-methyl-norsalsolinol or norsalsolinol. Following an initial rapid decline in tyrosine hydroxylation, the residual activity remained stable for 5 h at 37 degrees C. Phosphorylation by protein kinase A facilitates the release of bound catecholamines and is the most prominent mechanism of tyrosine hydroxylase reactivation. Protein kinase A also fully restored enzyme activity after incubation with N-methyl-norsalsolinol, demonstrating that tyrosine hydroxylase inhibition by 6,7-dihydroxylated tetrahydroisoquinolines mimics all essential aspects of catecholamine end-product regulation. Increased levels of N-methyl-norsalsolinol and related tetrahydroisoquinolines are therefore likely to accelerate dopamine depletion in Parkinson's disease.

• Authors: Joachim Scholz, Karen Toska, Alexander Luborzewski, Astrid Maass, Volker Schünemann, Jan Haavik, Andreas Moser
• Journal: The FEBS journal (FEBS J) Vol. 275 Issue 9 Pg. 2109-21 (May 2008) ISSN: 1742-464X [Print] England
• PMID: 18355318 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Catecholamines
• Enzyme Inhibitors
• Protein Isoforms
• Recombinant Proteins
• Tetrahydroisoquinolines
• Tyrosine 3-Monooxygenase

Topics

• Binding Sites
• Catecholamines (pharmacology)
• Crystallography, X-Ray
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Feedback, Physiological
• Humans
• Models, Chemical
• Molecular Structure
• Oxidation-Reduction
• Parkinson Disease (metabolism)
• Protein Binding
• Protein Conformation
• Protein Isoforms (chemistry, genetics, metabolism)
• Protein Structure, Tertiary
• Recombinant Proteins (metabolism)
• Temperature
• Tetrahydroisoquinolines (chemistry, metabolism, pharmacology)
• Time Factors
• Tyrosine 3-Monooxygenase (antagonists & inhibitors)